ZA200005294B

ZA200005294B - Process for preparing 4-substituted-1H-indole-3-glyoxamides.

Info

Publication number: ZA200005294B
Application number: ZA200005294A
Authority: ZA
Inventors: Benjamin Alan Anderson; Nancy Kay Harn
Original assignee: Lilly Co Eli
Priority date: 1998-04-17
Filing date: 2000-09-29
Publication date: 2001-10-01
Also published as: DZ2770A1; HUP0101344A3; AU750368B2; EA200001076A1; NO20005148L; WO1999054300A1; AR015767A1; HUP0101344A2; IL138827A0; HK1039120A1; CO5080803A1; EP1071663A1; TR200002999T2; ID26021A; NZ507175A; AU3564899A; BR9909697A; KR20010042741A; SV1999000043A; CN1305459A

Description

PE K

. ~ WO 99/54300 PCT/US99/08332 -1-

PROCESS FOR PREPARING 4-SUBSTITUTED-1H-INDOLE-3-GLYOXAMIDES

This invention relates to a process for preparing certain 1H-indole-3-glyoxamides useful for inhibiting sPLAj mediated release of fatty acids for conditions such as septic shock and intermediates useful in the preparation of such compounds.

Certain 1H-indole-3-glyoxamides are known to be potent and selective inhibitors of mammalian sPLA; useful for treating diseases, such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related sPLA; induced diseases. EPO publication No. 0675110, for example, discloses such compounds.

Various patents and publications describe processes for making these compounds using 4-hydroxy indole intermediates.

The article, "Recherches en serie indolique. VI sur tryptamines substituees", by Marc Julia, Jean Igolen and

Hanne Igolen, Bull. Soc. Chim. France, 1962, pp. 1060-1068, describes certain indole-3-glyoxylamides and their conversion to tryptamine derivatives.

The article, "2-Aryl-3-Indoleglyoxylamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR}" by E. Romeo, et al.,

The Journal of Pharmacology and Experimental Therapeutics,

Vol. 262, No. 3, (pp. 971-978) describes certain 2-aryl-3- indolglyoxylamides having research applications in mammalian central nervous systems.

The abstract, "Fragmentation of N-benzylindoles in

Mass Spectrometry"; Chemical Abstracts, Vol. 67, 1967, 73028h, reports various benzyl substituted phenols including y $ ° those having glyoxylamide groups at the 3 position of the indole nucleus.

U.S. Patent No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus.

U.S. Patent No. 3,351,630 describes alpha- substituted 3-indolyl acetic acid compounds and their preparation inclusive of glyoxylamide intermediates.

U.S. Patent No. 2,825,734 describes the preparation of 3-(2-amino-l-hydroxyethyl) indoles using 3- indoleglyoxylamide intermediates such as l-phenethyl-2- ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30). i U.S. Patent No. 4,397,850 prepares isoxazolyl indolamines using glyoxylamide indoles as intermediates.

U.S. Patent No. 3,801,594 describes analgesics prepared using 3-indoleglyoxylamide intermediates.

The article, "No. 565. - Inhibiteurs d'enzymes.

XII. - Preparation de (propargylamino-2 ethyl)-3 indoles" by

A. Alemanhy, E. Fernandez Alvarez, O. Nieto Lopey and M.E.

Rubio Herraez; Bulletin De La Societe Chimigque De France, 1974, No. 12, pp. 2883-2888, describes various indolyl-3 glyoxamides which are hydrogen substituted on the 6-membered ring of the indole nucleus.

The article "Indol-Umlagerung von l-Diphenylamino- 2,3-dihydro-2, 3-pyrrolidonen" by Gert Kollenz and Christa

Labes; Liebigs Ann. Chem., 1975, pp. 1979-1983, describes phenyl substituted 3-glyoxylamides.

Many of these processes employ a 4-hydroxy indole intermediate. For example U.S. Patent No. 5,654,326 U.S., herein incorporated by reference in its entirety, discloses a process for preparing 4-substituted-1H-indole-3-glyoxamide derivatives comprising reacting an appropriately substituted

‘a * \ b WO 99/54300 PCT/US99/08332 \ -3- 4-methoxyindole (prepared as described by Clark, R.D. et al., Synthesis, 1991, pp 871-878, the disclosures of which are herein incorporated by reference) with sodium hydride in dimethylformamide at room temperature (20-25°C) then treating with arylmethyl halide at ambient temperatures to give the l-arylmethylindole which is O-demethylated using boron tribromide in methylene chloride (Tsung-Ying Shem and

Charles A. Winter, Adv. Drug Res., 1877, 12, 176, the disclosure of which is incorporated by reference} to give the 4-hydroxyindole. Alkylation of the hydroxy indole is achieved with an alpha bromoalkanoic acid ester in dimethyl formamide using sodium hydride as a base.

Conversion to the glyoxamide is achieved by reacting the «- { (indol-4-yl)oxylalkanoic acid ester first with oxalyl chloride, then with ammonia, followed by hydrolysis with sodium hydroxide in methanol.

The process for preparing 4-substituted-1H-indole- 3-glyoxamide derivatives, as set forth above, has utility.

However, this process uses expensive reagents and environmentally hazardous organic solvents, produces furan containing by-products and results in a relatively low yield of desired product.

In an alternate preparation an appropriately substituted proprionylacetate is halogenated with sulfuryl chloride. The halogenated intermediate is hydrolyzed and decarboxylated by treatment with hydrochloric acid then reacted with an appropriately substituted cyclohexane dione.

Treatment of the alkylated dione with an appropriate amine affords a 4-keto-indole which is oxidized by refluxing in a high-boiling polar hydrocarbon solvent such as carbitol in the presence of a catalyst, such as palladium on carbon, to prepare the 4-hydroxyindole which may then be alkylated and converted to the desired glyoxamide as described above.

* PY ~ ~-4- .

This process however is limited by the required high temperature oxidation and requires recovery of a precious metal catalyst.

While the methods described above for preparing the 4- hydroxy indole intermediate are satisfactory, a more efficient transformation is desirable.

The present invention provides an improved process for preparing lH-indole-3-glyoxamides. The process of the present invention can be performed with inexpensive, readily available, reagents under milder conditions and resulting in better overall yield. In addition, the present process allows for transformation with a wider variety of substituents on the indole platform. Other objects, features and advantages of the present invention will become

RN 15 apparent from the subsequent description and the appended claims.

The present invention provides a process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof;

R'CH, AN 4 \ gt

R

S

R N, (1)

R wherein: }

Rl is selected from the group consisting of C7-Cpg alkyl;

¢ ‘» ) I a WO 99/54300 PCT/US99/08332 f -5- (R"), ' —CH, ene. —C) , and aX.

Rr ’ wherein;

R10 is selected from the group consisting of halo, C3-Cjgq alkyl, C1-Cjg alkoxy, -S-(C3-Cjp alkyl) and halo(C1-Cig)alkyl, and t is an integer from 0 to 5 both inclusive;

RZ is selected from the group consisting of hydrogen, halo, .

C1-C3 alkyl, C3-C4 cycloalkyl, C3-Cq cycloalkenyl, ~0-(C1-C, alkyl), -S-(C1-Cp alkyl), aryl, aryloxy, and

HET;

R4 is selected from the group consisting of -COpH, -SO3H, and -P (0) (OH), or salt or prodrug derivatives thereof; and

RY is selected from the group consisting of hydrogen, (Ci-

Ce)alkyl, (C1-Cg)alkoxy, halo (C3-Cg)alkoxy, halo(Cp-

Cg) alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of: a) halogenating a compound of formula X 8

J

X

[} bh

EY

-6- . where R8 is (C1-Cg)alkyl, aryl or HET; with 502Cl2 to form a compound of formula IX 8

R

A

Cl IX; b) hydrolyzing and decarboxylating a compound of formula IX 0 8

R

~o Rr?

Cl IX . 10 to form a compound of formula VIII } O . a J 2

R yrii1; c) alkylating a compound of formula VII

O .

QL

R Oy11 with a compound of formula VIII 0 ar 2

Rovirz to form a compound of formula VI

’ »

Y WO 99/54300 PCT/US99/08332 2

R o O

S

R VI; d) aminating and dehydrating a compound of formula VI oO

Rr? 5 0 ©

R VI with an amine of the formula RINH, in the presence of a solvent that forms an azeotrope with water to form a compound of formula V 2 g N R

R® by

R Vv; e) oxidizing a compound of formula V 0 1

R v by heating with a base and a compound of the formula RSOX where R is -(Ci;—-Ce¢)alkyl or aryl and X is -(C;-Cs}alkoxy, halo or -0CO;(C;-C¢)alkyl to form a compound of formula IV - rR’ yor

R IV; f) alkylating a compound of the formula IV

H

5 N rR’ y ta

R Iv with an alkylating agent of the formula XCHpR4a where X is a

N leaving group and R42 is -COoR4Db, -so3r4b, -p(0) (OR4DP),, or -

P (0) (or4P)H, where R4D is an acid protecting group, to form a compound of formula III 4a - 2

RNR

R IIL; g) reacting a compound of formula III

’ » ~ WO 99/54300 PCT/US99/08332 -0- -

H.R*®

A ] ~~, 2

R® Y R

R III with oxalyl chloride and ammonia to form a compound of formula II

H,R**Q 0 :

R® N R® 1

R 11; h) optionally hydrolyzing a compound of formula II - 4aQ

CH,R oO

Lo" 2 5 N R

R I

R II to form a compound of formula I; and i) optionally salifying a compound of formula I.

In another embodiment of the invention is provided a process for preparing a compound of formula I comprising the steps of: a) oxidizing a compound of the formula V

- . J§

R® Y R

R v by heating with a base and a compound of the formula RSOX where R is = (C,-Cg)alkyl or aryl and X is -(Cy;-C¢) alkoxy, halo or -0CQ;(Ci;-Ce)alkyl to form a compound of formula IV

OH rR’ | N rR’ _ ly : R Iv; b) alkylating a compound of the formula IV : 10

OH yl

R® NF

R Iv : with an alkylating agent of the formula XCHpR42 where X is a leaving group and R42 is -CO,R4D, -so3Réb, -P (0) (orb) 5 or -pP(0) (OR4P)H, where RAD is an acid protecting group, to form a compound of formula III

+ WO 99/54300 PCT/US99/08332 a

Rr’ ¥ R’

R III; c) reacting a compound of formula III a 2

R> yor

R III with oxalyl chloride and ammonia to form a compound of formula II cH, R"*Q )

NH, 2 rR’ YR

R II; and d) optionally hydrolyzing a compound of formula II

H,R*"Q oO ( CL 2 5 N R

R ly

R II to form a compound of formula I; and e) optionally salifying a compound of formula I.

Re

L

-12-~- :

The compounds of the invention employ certain defining terms as follows:

As used herein, the term, “alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, and the like.

The term "(C1-Ci10) alkoxy", as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxyl, heptoxy, hexoxy, octoxy, nonoxy, decoxy and _ like groups, attached to the remainder of the molecule by the oxygen atom. :

The term " (C3-C4) cycloalkyl" includes cyclopropyl, and cyclobutyl groups : The term “C3-C4 cycloalkenyl” includes a cyclopropenyl or cyclobutenyl ring having a double bond at the 1- or 2- position.

The term “halo” means fluoro, chloro, bromo or iodo.

The term “halo (C1-C10)alkyl” means a (C1-C10)alkyl group, substituted with from 1 to 3 halo atoms, attached to the remainder of the molecule by the alkyl group. The term halo (C1-C10) alkyl includes the term halo(C2-Ce¢)alkyl.

The term “halo (C1-Ce) alkoxy” means a halo- substituted alkoxy group which group is attached to the remainder of the molecule at the oxygen of the alkoxy.

The term "aryl" means a group having the ring structure characteristic of benzene, pentalene, indene, naphthalene, azulene, heptalene, phenanthrene, anthracene, etc. The aryl group may be optionally substituted with 1 to 3 substituents selected from the group w av WO 99/54300 PCT/US99/08332

I

-13~ . consisting of (C1-Cg)alkyl (preferably methyl), (C1-Cg) alkoxy or halo (preferable fluorine or chlorine).

The term “aryloxy” means an aryl group attached to the remainder of the molecule by an oxygen linker.

The term "leaving group" means a substituent with an unshared electron pair that departs from the substrate in a nucleophilic substitution reaction. The term "leaving group" includes halo, sulfonate, acetate and the like.

The term HET includes pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, pyrazole, furan, thiophene, thiazole, isothiazole, oxadiazole, thiadiazole, imidazole, triazole and tetrazole. The heterocyclic ring can be attached to the remainder of the molecule by any carbon in the heterocyclic ring.

The salts of the compounds of formula I are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic. ) : functional groups various salts may be formed which ‘are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include but are not limited to the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like.

Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.

Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., “Pharmaceutical

Salts,” J. Phar. Sci., 66: 1-19 (1977)).

-1 4 - _

The term "acid protecting group" is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an acid group from participating in a reaction carried cut on some other

S functional group of the molecule, but which can be removed when it is desired to do so. Such groups are discussed by

T.W. Greene in chapter 5 of Protective Groups in Organic

Synthesis, John Wiley and Sons, New York, 1981, incorporated herein by reference in its entirety.

Examples of acid protecting groups includes ester or amide derivatives of the acid group, such as methyl, methoxymethyl, methyl-thiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenylaryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, t-butyl, - 15 cyclopentyl, triphenylmethyl, p-bromobenzyl, trimethylsilyl,

N,N-dimethyl, pyrrolidinyl, piperidinyl or o-nitroanilide.

A preferred acid-protecting group is methyl.

Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard,

H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, such as, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic esters {e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic esters derived from acidic groups pendent on the compounds of this av} WO 99/54300 PCT/US99/08332 invention are preferred prodrugs. Other preferred esters include morpholinoethyloxy, diethylglycolamide and diethylaminocarbonylmethoxy

In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or { (alkoxycarbonyl) oxy) alkyl esters.

A preferred group of compounds of formula I prepared by the process of the instant invention are those wherein: (RY), —en.

Rl is ;

R2 is halo, cyclopropyl, methyl, ethyl, propyl, O-methyl or

S-methyl;

RY is -COpH; and : 15 RS, R® and R7 are H.

Compounds which can be made by the process of the . instant invention include: ((3-(2-amino-1,2-dioxyethyl)-2-methyl-1-(phenylmethyl)-1H- indol-4~-yl)oxy)acetic acid; dl-2-((3-(2-amino-1,2-dioxyethyl)=-2-methyl-1~(phenylmethyl)- 1H-indol-4-yl) oxy) propanoic acid; {{3-(2-amino-1, 2-dioxyethyl)-1-(((1,1’-biphenyl)-2- ylmethyl}-2-methyl-1H-indol-4-yl)oxy)acetic acid; {{3-(2-amino-1, 2-dioxyethyl)-1~( (1, 1’ -biphenyl)-3-ylmethyl) - 2-methyl-1H-indol-4-yl)oxy) acetic acid; } ((3-(2-amino-1, 2-dioxyethyl}-1-((1,1’-biphenyl)-4-ylmethyl)- 2-methyl-1H-indol-4-yl) oxy)acetic acid; {(3-(2~amino-1, 2-dioxyethyl)-1-{( (2, 6—-dichlorophenyl)methyl) - 2-methyl-1H-indol-4-yl) oxy)acetic acid; {(3-(2~amino-1, 2-dioxyethyl) -1- (4-flucrophenyl)methyl)-2- methyl-1H-indol-4-yl)oxy)acetic acid:

({(3-(2-amino-1,2~-dioxyethyl)-2-methyl-1- ( (naphthalenyl)methyl)-1H-indol-4-yl)oxy)acetic acid; ((3-(2-amino-1,2-dioxyethyl)-2-ethyl-1-(phenylmethyl)-1H~ indol-4-yl)oxy)acetic acid; ((3-(2-amino-1, 2~dioxyethyl)-1-( (3-chlorophenylmethyl)-2- ethyl-1H-indol-4-yl)oxy)acetic acid; ((3-(2-amino-1,2~dioxyethyl}-1-((1,1’biphenyl)-2-ylmethyl)- 2-ethyl-1H-indol-4-yl)oxy)acetic acid; {(3=(2-amino-1, 2-dioxyethyl)-1-((1,1’-biphenyl) -2-ylmethyl)- 2-propyl—-1H-indol-4-yl) oxy) acetic acid; ’ {{3-(2-amino-1, 2-dioxyethyl) -2-cyclopropyl-1- (phenylmethyl)- 1H-indol-4-yl)oxy)acetic acid; ( (3-(2~amino-1,2-dioxyethyl)-1-((1,1'biphenyl)-2-ylmethyl)- 2-cyclopropyl-1H-indol-4-yl)oxy) acetic acid; 4-((3-(2-amino~1,2-dioxyethyl)-=2-ethyl-1- (phenylmethyl}-1H- : indol-4-yl)oxy)butanoic acid; { (3~(2-amino-1,2-dioxyethyl)-2-ethyl-1- (phenylmethyl)-1H- indol-4-yl)oxyacetic acid; ((-3- (2-amino-1, 2-dioxyethyl) -2-ethyl-6-methyl-1- {phenylmethyl)-1H-indol-4-yl)oxy) acetic acid; ((=3=(2-amino-1, 2-dioxyethyl) -2, 6-dimethyl-1- (phenylmethyl)- 1H-indol-4-yl)oxy) acetic acid; ((3-(2-amino-1, 2-dioxyethyl)-2-methyl-1- (phenylmethyl)-1H- indol-4-yl) oxy) acetic acid; ((3-(2-amino-1, 2-dioxyethyl) -6-ethyl-2-methyl-1- (phenylmethyl)-1H-indol-4-yl)oxy)acetic acid; ((3-(2-amino-1,2-dioxyethyl)-2, 6-diethyl-1- (phenylnmethyl) - 1H-indol~4-yl) oxy) acetic acid; ((3-(2-amino-1, 2-dioxyethyl) -2-methyl-6-phenoxy-1- (phenylmethyl)-1H-indol-4-yl) oxy) acetic acid; ( (3- (aminooxoacetyl)-2-ethyl-6-methyl-1- (phenylmethyl) -1H- indol-4-yl)oxy)acetic acid; and

Vv WO 99/54300 PCT/US99/08332 -17~ BN { (3- (2-amino-1, 2-dioxyethyl)-2-ethyl-6-phenoxy-1- (phenylmethyl)~1H-indol-4-yl) oxy) acetic acid or a pharmaceutically acceptable salt thereof.

Of these compounds, preferred compounds include: {(3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl)-1H- indol-4-yl)oxyacetic acid; ( (-3-(2-amino-1,2-dioxyethyl)-2-ethyl-6-methyl-1- (phenylmethyl) -1H-indol-4-yl)oxy) acetic acid; {(=3-(2-amino-1, 2-dioxyethyl}-2, 6-dimethyl~1- (phenylmethyl)- 1B-indol-4-yl) oxy} acetic acid; ((3-(2-amino-1, 2-dioxyethyl)~2-methyl-1-{phenylmethyl}-1H- indol-4-yl)oxy)acetic acid; ((3-(2-amino-1, 2-dioxyethyl)-6-ethyl-2-methyl-1- (phenylmethyl)-1H-indol-4-yl)oxy) acetic acid; ((3=(2-amino-1, 2-dioxyethyl)-2, 6~diethyl-1- (phenylmethyl)- 1H-indol~4-yl) oxy) acetic acid; - } { (3~ (2-amino-1, 2~dioxyethyl) -2-methyl-6-phenoxy-1- (phenylmethyl)-1H-indol-4-yl)oxy)acetic acid; ({3- (aminooxoacetyl)-2-ethyl-6-methyl-1- (phenylmethyl)-1H- indol-4-yl)oxy)acetic acid; and ((3-(2-amino-1, 2-dioxyethyl)-2-ethyl-6-phenoxy-1- (phenylmethyl) -1H-indol-4-yl)oxy) acetic acid or a pharmaceutically acceptable salt thereof. )

Of these compounds even more preferred are: {(3-(2-amino-1, 2-dioxyethyl) -2-methyl-1- (phenylmethyl) -1H- indol-4-yl)oxy)acetic acid and ((3-(2-amino-1,2-dioxyethyl)- 2-ethyl-1- (phenylmethyl)-1H-indol-4-yl)oxyacetic acid.

The most preferred compound which can be prepared by the instant process is ((3-{2-amino-1,2-dioxyethyl)-2- ethyl-1- (phenylmethyl)-1H-indol-4-yl)oxyacetic acid or a pharmaceutically acceptable salt thereof.

The process of the present invention provides an improved method for synthesizing the compounds of formula I using inexpensive, readily available reagents as shown in

Scheme I as follows.

Scheme I 9 H a b 2 : rR V R 2 y rR?

R rR} (vV) (IV) 4a ) : CH, R cH,R**Q oO 4 Cc da

Eanes, NH, — 2 rR’ y oR RS N~ “R’

Rr Vy

R

III

(111) (11)

HR 0] 0] 2

NH

2

RTC N OR

R

(I)

Ketone (V) is dissolved in a suitable solvent preferably an aprotic solvent such as THF. Other suitable solvents include but are not limited to DMF, dioxane, or toluene.

The substrate/solvent solution may be sonicated or heated slightly, if necessary to facilitate dissolution.

2; WO 99/54300 PCT/US99/08332

The amount of solvent used should be sufficient to ensure that all compounds stay in solution until the desired reaction is complete.

The solution is treated with a base, preferably a strong base such as sodium hydride, then with a sulfinating agent of the formula oy where R is -(Cy-Ce¢)alkyl, aryl or substituted aryl and X is {C;-C¢) alkoxy, halo or -0CO,(Ci-

Ce¢)alkyl. The sulfinating reagent may be prepared according to the procedure of J.W. Wilt et al., J. Org. Chem, 1367, 32, 2097. Preferred sulfinating agents include methyl p- tolyl sulfinate, methylbenzene sulfinate or p-toluylsulfinic isobutyric anhydride. Other suitable bases include but are not limited to LDA, sodium methoxide, or potassium methoxide. Preferably two equivalents of base are used.

Preferably, when sodium hydride is employed, the base is added before the sulfinating reagent. The order of addition of reagents is not important when sodium methoxide is used.

The reaction may be conducted at temperatures from about 25°C to reflux, preferably at reflux and is substantially complete in from one to 24 hours.

The amount of sulfinating reagent is not critical, however, the reaction is best accomplished using a molar equivalent or excess relative to the pyrrole starting material (1).

The above reactions may be run as a “one pot” process with the reactants added to the reaction vessel in the order given above.

Dioxane is a preferred solvent in a “one part” process. THF and toluene, respectively, are preferred solvents if a “two pot” process is employed as depicted in scheme I(a), below.

The intermediates IV can be isolated and purified using standard crystallization or chromatographic procedures.

B Standard analytical techniques such as TLC or HPLC can be used to monitor the reactions in order to determine when the starting materials and intermediates are converted to product.

In an alternate preparation, the sulfinating reagent can be replaced with a disulfide compound of the formula R¥*SSR** where R?® is alkyl or aryl. Oxidation of the sulfide intermediate can then be readily achieved using an appropriate oxidizing reagent such as hydrogen peroxide or m—chloroperbenzoic acid.

Indole (IV) may then be readily alkylated with an alkylating agent of the formula XCHR42 where X is a suitable leaving group and R42 is a protected carboxy, sulfonyl or phosphonyl acid group, preferably protected with : an ester group, in the presence of a base. Methyl bromoacetate is a preferred alkylating agent. Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or potassium hydroxide. Potassium carbonate is preferred. The amount of alkylating agent is not critical, however, the reaction is best accomplished using a molar excess of alkylating agent relative to the starting material. The reaction is preferably carried out in an organic solvent such as acetone, acetonitrile or dimethylformanide. Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, acetonitrile, toluene, or t-butyl methylether. The reaction is conducted at temperatures of from about 0° to 100°C, preferably at ambient temperature, and is substantially complete in about 1 to 24 hours depending on the reactants employed and such conditions as reaction temperature.

2} WO 99/54300 PCT/US99/08332

Optionally, a phase transfer reagent such as tetrabutylammoniumbromide may be employed.

Preparation of glyoxamide II is readily achieved in a two step process by first treating intermediate III with oxalyl chloride at concentrations from about 0.2 to 1.5mmol, preferably at equimolar concentrations relative to the starting material. Solvents such as methylene chloride, chloroform, trichloroethylene, carbon tetrachloride, ether or toluene are preferred. Temperatures from about -20°C to ambient temperature are suitable, preferably about -5°C.

In the second step, the solution is treated with ammonia; either bubbled in as a gas or, preferably, using a molar excess of 30% aqueous ammonia. The reaction is typically conducted at temperatures from about -25°C to 25°C, preferably at about -2°C to 0°C, and is substantially complete in 10 minutes to an hour. i

Hydrolysis of II is achieved using a base such as potassium hydroxide, lithium hydroxide or sodium hydroxide, preferably sodium hydroxide, in a lower alcohol solvent, such as methanol, ethanol, isopropanol, etc., or solvents such as tetrahydrofuran, dioxane and acetone.

Using standard analytical techniques, such as

HPLC, the reactions of Scheme I can be monitored to determine when starting materials and intermediates are converted to product.

Scheme I(a), below, illustrates the two pot procedure, described above, for the preparation of intermediate IV. Intermediate IV(a) can be isolated and purified using standard chromatographic procedures.

Claims

1. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof rico 9 ° NH WC s R 1 (I) wherein: Rl is selected from the group consisting of C3-Cpq alkyl; (R'), ’ —CH, I) SETN gp J —anf 1) ; 4 10 R where; R'® is selected from the group consisting of halo, C1-Cjyg alkyl, C1-Cyo alkoxy, -S-(C3-Cyp alkyl) and halo(Ci-Cyp0)alkyl, and t is an integer from 0 to 5 both inclusive: R’ is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3~C4 cycloalkenyl, -0-(C1-C2 alkyl), -S-(Cj-Cp alkyl), aryl, aryloxy, and N HET; Lo “ . I “ow mm sem

\ 4 WO 99/54300 PCT/US99/08332 —- 2 9 - . R' is selected from the group consisting of -CO,H, -SO03H, and -P(0) (OH) or salt or prodrug derivatives thereof; and R’ is selected from the group consisting of hydrogen, (Cq- Cg)alkyl, (C1-Cg)alkoxy, halo (C1-Cg) alkoxy, halo(Cp- Cg) alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of a) halogenating a compound of formula X

8 R JI ~ o rR’ X ’ . where R8 is (C;-Cg)alkyl, aryl or HET; with S02Cly to form a compound of formula IX - . 8 R ~ A cl IX;

b) hydrolyzing and decarboxylating a compound of formula IX 8 R ~ AL, cl TX to form a compound of formula VIII a J 2 Royr1z; c) alkylating a compound of formula VII 0] 0 R Ovir with a compound of formula VIII a J 2 R yz

10 . to form a compound of formula VI RZ o 6) 5 R Vi; d) aminating and dehydrating a compound of formula VI RZ 5 [@] © R VI

Y WO 99/54300 PCT/US99/08332 with an amine of the formula RINH, in the presence of a solvent that forms an azeotrope with water to form a compound of formula V 0 2 N R R® I, R Vi e) oxidizing a compound of formula V 0 4 y ‘R® ly R Vv by heating with a base and a sulfinylating reagent of the formula RSOX where R is -{C;-Cg¢)alkyl or aryl and X is -{C;- C¢) alkoxy, halo or -0CO;(C,-Cg)alkyl to form a compound of formula IV

~ . | ~ 2 rR’ y OR R Iv; f) alkylating a compound of the formula IV

H N rR’ Ia R Iv with an alkylating agent of the formula XCHoR42 where X is a leaving group and R42 is -CO,R4b, -so3r4P, -p(0) (cR4DP),, 5 or -P(0) (0OR4P)H, where R4P is an acid protecting group, to form a compound of formula III 4a - 2 Rr’ yO R 111; g) reacting a compound of formula III ocH,R"® Sul R® ¥, R R III with oxalyl chloride and ammonia to form a compound of formula II H,R"*Q 0 R® N R® 1 R 11;

v WO 99/54300 PCT/US99/08332 h) optionally hydrolyzing a compound of formula II H,R**Q 0 oT 2 R® Y. R R II to form a compound of formula I; and i) optionally salifying a compound of formula I.

2. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof rR'cu,0 Po NH 2 N—r? 5 R , (1) R wherein: Rl is selected from the group consisting of C7-Cpp alkyl; (R*), — (CH); I —CH, RL ’

~34- ’ where

R10 is selected from the group consisting of halo, C1-Cig alkyl, C1-Cjg alkoxy, -5-(C;-Cjyp alkyl) and halo (C1-Cjp)alkyl, and t is an integer from 0 to 5 both inclusive;

R is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-Cq cycloalkenyl, -0-(C1-Cp alkyl), -S-(C3-Cp alkyl), aryl, aryloxy, and HET;

R' is selected from the group consisting of -COzH, -SO3H, and -P(0) (OH) 2 or salt or prodrug derivatives thereof; and rR’ is selected from the group consisting of hydrogen, (Cqp- Cg) alkyl, (C1-Cg)alkoxy, halo(C3-Cg)alkoxy, halo (Cp-

Cg)alkyl, bromo, chloro, fluoro, iodo and aryl; : : which process comprises the steps of e) oxidizing a compound of formula V R v by heating with a base and a compound of the formula RSOX where R is -(C,-Cs)alkyl or aryl and X is -(C;~C¢}alkoxy,

halo or -0C0,(C,-C¢) alkyl to form a compound of formula IV

— i

\ 4 WO 99/54300 PCT/US99/08332

A. R’ N R® [PY R Iv; £) alkylating a compound of the formula IV OH 1 y "R* ly R Iv with an alkylating agent of the formula XCH,R42 where X is a leaving group and R42 is -CozR4Db, -so3r4b, -p(0) (0R4P);,, or - ] p (0) (OR4P)H, where R4P is an acid protecting group, to form a compound of formula III - 2 5 N R R ly R 111; g) reacting a compound of formula III 4a 5 2 R® ¥ OR R III »

\! — 3 6— R with oxalyl chloride and ammonia to form a compound of formula II OcH,R"*Q 0 Im R® NTR 1 R 11; h) optionally hydrolyzing a compound of formula II cH,R"*Q 0 2 5 N R R ly R II to form a compound of formula I; and i) optionally salifying a compound of formula I.; and e) optionally salifying a compound of formula I.

3. The process of Claim 1 or 2 where the sulfinating reagent is p-tolulylsulfiniciscobutyric anhydride. 4, The process of any one of Claims 1 to 3 which prepares ((3-(2-amino-1,2-dioxyethyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl) oxy) acetic acid.

[] 4 WO 99/54300 PCT/US99/08332

5. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof R'cH,p ° NH, Nr? R® XN, (1) R wherein: Rl is selected from the group consisting of Cg-Cpg alkyl; (R*), 14 —CH, enon —) , and - —aft 1) ; Rr? where; R' is selected from the group consisting of halo, C1-Cig alkyl, C1-Cjo alkoxy, -S-(C1-Cjp alkyl) and halo (C1-Cip)alkyl, and t is an integer from 0 to 5 both inclusive; R’ is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0-(C1-C2 alkyl), -S-(C3-Cz alkyl), aryl, aryloxy, and HET;

» . ~38- ; R! is selected from the group consisting of -CO3H, -SO3H, and -P(0) (OH), or salt or prodrug derivatives thereof; and Rr’ is selected from the group consisting of hydrogen, (Ci- Cg) alkyl, (C;-Cg)alkoxy, halo(C;-Cg)alkoxy, halo(Cp- Cg)alkyl, bromo, chloro, fluoro, iodo and aryl: when made by the process of Claim 1.

6. A process for preparing a compound of formula I or a pharmaceutically acceptable salt or prodrug derivative thereof _ R'cHo Q P NH N_g? 5 R (I) Rr wherein: Rl is selected from the group consisting of C7-Czq alkyl; (R*), — (CHy) 3 4 —CH, Onin). —erf 1) ; RC ’ where; 10 R is selected from the group consisting of halo, C3-Cyp alkyl, C1-Cjqg alkoxy, -S-(C;3-Cjp alkyl) and

I - -39~- hale (C1-Cjplalkyl, and t is an integer from 0 to 5S both inclusive; R’ is selected from the group consisting of hydrogen, hale, C1-C3 alkyl, C3-Cq cycloalkyl, C3~C4 cycloalkenyl, =0-{C1-C2 alkyl), -5-(Cy-Cy alkyl), azyl, aryloxy, and HET; R* is selected from the group consisting of —COzH, -SOsH, and -P (0) (OH) or salt or prodrug derivatives thereof; and r’ is selected from the group consisting of hydrogen, {C1- Celalkyl, (Cy-Cg)alkoxy, halo (Cy-Cg)alkoxy, halo (Cy- Celalkyl, bromo, chloro, fluoro, iodo and aryl; } substantially as herein before described with reference to any one of the Examples.

7. A process according to Claim 1, or Claim 2, or Claim 5, or Claim 6, substantially as herein described and illustrated.

8. A new process for preparing a compound, substantially as herein described. . AMENDED SHEET